The gender-specific risk to liver toxicity and cancer of flounder (Platichthys flesus (L.)) at the German Wadden Sea coast.

Flatfish living in coastal areas are chronically exposed to a wide range of toxic and (pro)carcinogenic compounds derived from agriculture and industry. Flounder (Platichthys flesus (L.)) is the main target species for monitoring health effects of contamination in North Sea and Baltic Sea since the species is abundant, benthic, and inhabits shallow waters such as the Wadden Seas and estuaries along salinity gradients into fresh water. Chemical analysis in the same livers as investigated for histopathology in the present study showed positive correlation between accumulation of certain organochlorines in liver and the extend of liver injury. Toxipathic liver changes including neoplasms in female and male flounder were analysed by macroscopic and light microscopic diagnosis during a five-year survey on the basis of internationally accepted criteria agreed upon during the European BEQUALM intercalibration of liver histopathology of flatfish. Hepatocellular carcinogenesis of wild flounder principally showed sequential changes similar to experimental chemical carcinogenesis in other fish species and mammals. These ranged from early foci of altered hepatocytes (vacuolated/clear/eosinophilic, basophilic cells) and the development of adenomas. With progression to hepatocellular carcinomas, livers of wild flounder entered a multistage phase of carcinogenesis comprising of early foci, hepatocellular adenomas and carcinomas, as observed in human liver cancers. Female flounder had three-fold higher frequencies of macroscopically visible neoplasms than males of the same age classes. Histopathological diagnosis showed that hepatocellular alterations in male flounder never developed further than stages of basophilic foci and adenomas, and never into malignancies. In females, tumors of hepatocellular origin clearly dominated, occurred alone and together with cancers of bile duct epithelial cells and endothelial cells (cholangio-carcinomas, angiosarcomas). Because mutations of relevant genes could not be identified in the liver cancers that were analysed in the present study, we conclude that epigenetic events initiate carcinogenesis. Therefore, we conclude that mitogenic carcinogens found in the Elbe estuary play a dominant role for cancer development in this flounder population. Furthermore, the lower availability of reducing power (NADPH) needed for detoxification reactions in females compared to males, together with annual upregulation of the highly potent promotor 17-beta-estradiol during sexual maturation, promote progression of preneoplastic foci of initiated cells to malignant cancers in females.